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A γ‐secretase inhibitor blocks Notch signaling in vivo and causes a severe neurogenic phenotype in zebrafish
Author(s) -
Geling Andrea,
Steiner Harald,
Willem Michael,
BallyCuif Laure,
Haass Christian
Publication year - 2002
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.1093/embo-reports/kvf124
Subject(s) - notch signaling pathway , zebrafish , presenilin , amyloid precursor protein secretase , microbiology and biotechnology , biology , signal transduction , hes3 signaling axis , gamma secretase , notch proteins , phenotype , amyloid precursor protein , alzheimer's disease , biochemistry , gene , medicine , disease
Inhibition of amyloid β‐peptide (Aβ) production by blocking γ‐secretase activity is at present one of the most promising therapeutic strategies to slow progression of Alzheimer's disease pathology. γ‐secretase inhibitors apparently block Aβ generation via interference with presenilin (PS) function. Besides being an essential component of the γ‐secretase complex, PS itself may be an aspartyl protease with γ‐secretase activity, which is not only required for Aβ production but also for a similar proteolytic process involved in Notch signaling. Here we demonstrate that treatment of zebrafish embryos with a known γ‐secretase inhibitor affects embryonic development in a manner indistinguishable from Notch signaling deficiencies at morphological, molecular and biochemical levels. This indicates severe side‐effects of γ‐secretase inhibitors in any Notch‐dependent cell fate decision and demonstrates that the zebrafish is an ideal vertebrate system to validate compounds that selectively affect Aβ production, but not Notch signaling, under in vivo conditions.